This project is designed to study, in elderly subjects, the consequences of ethanol consumption on in vivo utilization and metabolism of glucose. We hypothesize, that ethanol consumption in elderly subjects will increase their insulin resistance, reduce their glucose tolerance, and may cause overt diabetes mellitus. Our hypothesis is based on the observation that ethanol causes acute insulin resistance in young subjects. These individuals are able to overcome the ethanol induced insulin resistance by oversecretion of insulin. In contrast, pre- existing insulin resistance and compromised insulin secretory capacity may make it difficult for elderly subjects to cope with the additional burden of ethanol induced insulin resistance. We will test this hypothesis by comparing effects of ethanol on insulin sensitivity (measured with the euglycemic- hyperinsulinemic clamp technic) and on glucose tolerance (measured during intravenous glucose infusions) in elderly and young individuals who drink alcohol rarely (or not at all) and in elderly and young individuals who habitually drink alcohol in moderate amounts. To explore possible mechanisms for ethanol induced insulin resistance, we will study, in all study subjects, the effects of ethanol on intracellular pathways of glucose oxidation and storage. Rates of glucose disappearance from the extracellular space will be quantitated with the 3-3H-glucose isotope dilution method and with the euglycemic-hyperinsulinemic clamp technic. Rates of total body glucose oxidation will be determined by indirect calorimetry. Activities of key enzymes for glucose oxidation (pyruvate dehydrogenase), glycolysis (phosphofructokinase), and glycogen formation (glycogen synthase), and of key metabolites (acetyl-CoA, CoA-SH, glucose-6- phosphate, lactate, pyruvate, citrate, and glycogen) will be measured in muscle biopsies. To determine which effects are caused by ethanol or acetaldehyde and which by acetate or its metabolites, we will perform all these measurements during infusions of either glucose plus ethanol or glucose plus acetate. We hope that these studies will provide important information on the nutritional impact of ethanol and on its possible contributory role to the increase incidence of diabetes mellitus in the elderly.